Optically active valines are important starting materials for the production of pharmaceutical and agricultural products. L-valine is a key starting material for the production of valsartan, valganciclovir, ritonavir, and lopinavir, while D-valine is used in the production of valnemulin, a pleuromutilin antibiotic, and tau-fluvalinate, a synthetic pyrethroid. As one of the essential amino acids, L-valine also finds wide applications in human and animal nutrition.
Valine obtained by synthesis is a racemate (DL-form) and should be optically resolved. On the other hand, L-valine, obtained from hydrolysis of proteins or from fermentation of suitable microorganism, is often contaminated with other amino acids of similar chemical and physical properties, such as L-alanine, L-leucine, and L-isoleucine. The separation of L-valine from these contaminating amino acids remains a major challenge in the industry.
The conventional methods for resolving DL-valine include the following:
(1) Asymmetric hydrolysis of N-acetyl valine by acylase to yield L-valine and N-acetyl D-valine. Hydrolysis of N-acetyl D-valine with an acid yields D-valine.
(2) Direct resolution of DL-valine hydrochloride (U.S. Pat. No. 3,182,079 and No. 4,667,054) or DL-valine xylenesulfonate (JP 62096454A) by preferential crystallization to yield L-valine and D-valine.
(3) Resolution of DL-valine with optically active resolving agents such as N-acyl aspartic acid (U.S. Pat. No. 4,610,827), dibenzoyl-tartaric acid (CN 1477096A, CN101659622A), diacetyl-tartaric acid (CN 102796018B), 2-phenoxypropionic acid (JP 2006169158A), and phenylethanesulfonic acid (U.S. Pat. No. 4,519,955).
However, the enzymatic method mentioned in (1) is disadvantageous since it involves acetylation of DL-valine and requires the use of an expensive enzyme.
As for the resolution by preferential crystallization in (2), the process is difficult to control and problematic to scale up.
When the inventor of the present invention made a follow-up of the known processes using optically active resolving agents in (3), it is found that the processes are extremely disadvantageous for industrial practice. N-acyl-L-aspartic acid forms L-valine complex with poor selectivity and low yield. Even with repeated crystallization of the intermediate complex, the optical purity of L-valine remains unsatisfactory.
Dibenzoyl-L-tartaric acid and diacetyl-L-tartaric acid, while useful as resolving agents for DL-valine, are unstable under the working conditions and are partially hydrolyzed to tartaric acid, benzoic acid, and acetic acid. The recovery and recycling of these resolving agents are problematic, thus rendering the process economically disadvantageous.
Optically active 2-phenoxypropionic acid and 2-phenylethanesulfonci acid can only resolve DL-valine partially and in low optical purity. Moreover, these two resolving agents are expensive, commercially unavailable, and complicated to prepare.
To purify the crude L-valine to yield high purity L-valine, U.S. Pat. No. 5,689,001 and No. 6,072,083 disclose the use of p-isopropylbenzene sulfonic acid and p-ethylbenzene sulfonic acid, respectively, to form crystalline valine salts as intermediates. However, these two sulfonic acids are not selective and their salts with L-valine are quite soluble in water (7.8% and 14.5%, respectively). As a result, in the process of using these sulfonic acids, the recovery yield for L-valine is low and the purity of L-valine needs further improving for its use in the production of pharmaceuticals.
After devoted research for developing commercially advantageous methods for optical resolution of DL-valine and for the purification of L-valine, the present inventor has discovered that optically active N-benzoyl-L-alanine reacts selectively with L-valine to form a novel crystalline complex, L-valine N-benzoyl-L-alanine, comprised of 1 mole each of L-valine and N-benzoyl-L-alanine, even in the presence of D-valine, amino acids (e.g., alanine, leucine, isoleucine, serine, phenylalanine, tyrosine, methionine, aspartic acid, and glutamic acid), and other impurities found in synthetic DL-valine and in the crude L-valine from protein hydrolysate and fermentation. This finding has become the basis for the accomplishment of this invention.